ABSTRACT
Background: A disruption of the crosstalk between gut and lung has been implicated as a driver of severity during several respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We applied a multi-omic systems biology approach to investigate the potential link between loss of gut barrier integrity and Coronavirus disease 2019 (COVID-19) severity. Methods: We analyzed plasma samples from age and gender-matched COVID-19 patients (n=60) with varying disease severity (mild, moderate, and severe) and 20 SARS-CoV2 negative controls. We measured markers and drivers of tight junction permeability and microbial translocation using ELISA;inflammation and immune activation markers using ELISA and multiplex cytokine arrays;untargeted metabolomic and lipidomic analyses using mass spectrometry;and plasma glycomes using capillary electrophoresis and lectin microarray. False discovery rate (FDR) was calculated to account for multiple comparisons. Results: Our data indicate, first, that severe COVID-19 is associated with a dramatic increase in the level of zonulin (FDR<0.00001), the only known physiological driver of intestinal tight junction permeability. This increased permeability associated with translocation of both bacterial (LPS binding protein (LBP) levels) and fungal (β-glucan levels) products into blood (FDR<0.01). The degree of intestinal permeability and microbial translocation strongly correlated with increased systemic inflammation (correlations with IL-6 and other inflammatory cytokines and markers) (FDR>0.05). Second, levels of metabolomic and lipidomic markers of gut and gut microbiota functionality including citrulline (a marker of healthy gut;decreased), succinic acid, and tryptophan catabolism metabolites (markers of microbial dysbiosis;increased) were disrupted during severe COVID-19 (FDR<0.05). Finally, the gut microbiome is known to release enzymes that degrade plasma glycans, which regulate inflammation and complement activation. Indeed, severe COVID-19 was associated with loss of the anti-complement activation galactosylated glycans from plasma and IgG glycoproteins (FDR<0.05). Conclusion: Our data provide multiple layers of evidence that a previously unappreciated factor with significant clinical implications, disruption in gut barrier integrity, is a potential force that contributes to COVID-19 severity.